title: Glucocorticoid-induced TNF receptor family-related protein ligand regulates the migration of monocytes to the inflamed intestine.
abstract: Glucocorticoid-induced TNF receptor family-related protein (GITR) regulates the function of both T cells and antigen-presenting cells (APCs), while the function of GITR ligand (GITR-L) is largely unknown. Here we evaluate the role of GITR-L, whose expression is restricted to APCs, in the development of enterocolitis. On injecting naive CD4(+) T cells, GITR-L(-/-)Rag(-/-) mice develop a markedly milder colitis than Rag(-/-) mice, which correlates with a 50% reduction of Ly6C(+)CD11b(+)MHCII(+) macrophages in the lamina propria and mesenteric lymph nodes. The same result was observed in αCD40-induced acute colitis and during peritonitis, suggesting an altered monocyte migration. In line with these observations, the number of nondifferentiated monocytes was approximately 3-fold higher in the spleen of GITR-L(-/-)Rag(-/-) mice than in Rag(-/-) mice after αCD40 induction. Consistent with the dynamic change in the formation of an active angiotensin II type 1 receptor (AT1) dimer in GITR-L(-/-) splenic monocytes during intestinal inflammation, the migratory capability of splenic monocytes from GITR-L-deficient mice was impaired in an in vitro transwell migration assay. Conversely, αGITR-L reduces the number of splenic Ly6C(hi) monocytes, concomitantly with an increase in AT1 dimers. We conclude that GITR-L regulates the number of proinflammatory macrophages in sites of inflammation by controlling the egress of monocytes from the splenic reservoir.
authors.affiliation: 1Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, CLS-928, Boston, MA 02115, USA. G.L., gliao@bidmc.harvard.edu.
authors.forename: Gongxian
authors.initials: G
authors.lastname: Liao
authors.forename: Boaz
authors.initials: B
authors.lastname: van Driel
authors.forename: Erica
authors.initials: E
authors.lastname: Magelky
authors.forename: Michael S
authors.initials: MS
authors.lastname: O'Keeffe
authors.forename: Rene
authors.initials: R
authors.lastname: de Waal Malefyt
authors.forename: Pablo
authors.initials: P
authors.lastname: Engel
authors.forename: Roland W
authors.initials: RW
authors.lastname: Herzog
authors.forename: Emiko
authors.initials: E
authors.lastname: Mizoguchi
authors.forename: Atul K
authors.initials: AK
authors.lastname: Bhan
authors.forename: Cox
authors.initials: C
authors.lastname: Terhorst
mesh_terms: D000818:Animals; D019013:CD40 Antigens; D005938:Glucocorticoids / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*
chemical_list: D019013:CD40 Antigens; D005938:Glucocorticoids; D018124:Receptors, Tumor Necrosis Factor
keywords: GITR-L; TNFSF18; experimental colitis; macrophage